The role of macrophage migration inhibitory factor in maintaining the immune privilege at the fetal–maternal interface

Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the innate and adaptive immunity affecting the response and behavior of macrophages and lymphocytes. MIF is also implicated in other fundamental cellular processes including angiogenesis and cell proliferation. Several studies examined the expression of MIF in reproductive organs and tissues and its involvement in different aspects of human and animal reproduction. The goal of this review was to summarize these findings and discuss, in particular, the role of MIF in the maintenance of the immune privilege at the human fetal–maternal interface.     

Is macrophage migration inhibitory factor (MIF) the “control point” of vascular hypo-responsiveness in septic shock?

Macrophage migration inhibitory factor (MIF), a member of the cytokine family, is beginning to be recognized as a pleiotropic proinflammatory molecule. MIF exerts function via antagonistic regulation of glucocorticoids, inhibition to apoptosis-mediated p53, influence on vasodilator gas NO and inducible nitric oxide synthase (iNOS), feedback counter-regulation of complement C5a controlling MIF release, and interaction with major cations as well. Interestingly, aforementioned glucocorticoids, apoptosis, NO, iNOS, C5a, Ca2+, Mg2+, Na+, K+, and H+ that are greatly associated with vascular tone or vasomotion. Nevertheless, the elevated serum and cytosolic concentrations of MIF exactly affect all above facets in septic shock models and patients, during which vasodilation of the peripheral resistance vessels occurs, and accompanied with decreased responsiveness to vascular pressors. Thus MIF may bring into play as one of point-controlling proteins in the onset of sustained vascular hypo-reactivity during the process of septic shock.     

Glial cell line-derived neurotrophic factor in Purkinje cells of adult zebrafish: An autocrine mode of action?

Glial cell line-derived neurotrophic factor (GDNF) has a neuroprotective role in Purkinje cells of cerebellum, promoting the survival and the differentiation of these cells. Its signalling is mediated by a receptorial complex GFRalpha1/RET. In the brain of adult zebrafish (Danio rerio) we previously investigated GDNF expression and localization, but no data exist regarding GFRalpha1 and RET presence. Thus, the present study was designed to clarify the morphological relation between GDNF and its receptorial complex GFRalpha1/RET immunoreactivity in the cerebellum of adult zebrafish. The expression of gdnf, GFRalpha1 and ret genes was demonstrated in adult zebrafish cerebellum by a standard RT-PCR. The distribution of GDNF and its receptorial complex GFRalpha1/RET was examined by single and double immunocytochemical stainings. In the valvula and corpus cerebelli GDNF, GFRalpha1 and RET immunoreactivity was seen co-localized in Purkinje cells, identified morphologically and by using an antiserum against a specific marker for these cells, aldolase C enzyme. In the vestibulolateralis lobe, Purkinje neurons were lacking in both the eminentiae granulares and medial caudal lobe. These results demonstrated the expression of the GDNF receptorial complex in adult zebrafish cerebellum and suggest an autocrine mode of action of GDNF in Purkinje cells.     

Regulation of na?ve fetal T-cell migration by the chemokines Exodus-2 and Exodus-3.

We and other workers have recently isolated three novel CC chemokines termed Exodus-1/LARC/Mip-3alpha, Exodus-2/6Ckine/SLC/TCA4, and Exodus-3/Mip-3beta/CKbeta11/ELC. These chemokines share an amino terminal Asp-Cys-Cys-Leu sequence, unique among all chemokines. They also selectively regulate migration of adult T cells. Indeed, there is evidence that Exodus-2 and -3 are critical for adult T-cell adhesion to high endothelial venules in lymph nodes, a rate-limiting step for T-cell trafficking through nodal tissue. Less is known of the factors controlling migration of na?ve human fetal T cells. We tested whether these chemokines could regulate chemotaxis in cord blood T-cell populations, and compared that efficacy with normal peripheral blood adult T cells. The findings indicated that naive CD45RA+ cord blood T-cell migration is stimulated by Exodus-2 and -3, and CD4+ cord blood T cells are attracted preferentially by Exodus-2 or -3 as compared with CD8+. Exodus-2 and -3 are likely to be critical in regulating the flux of naive CD4 + fetal T-cell population of secondary lymphoid tissue.     

Tracing the origins of “fetal origins” of adult diseases: Programming by oxidative stress?

Too small size at birth (due to poor fetal growth and/or preterm delivery) has been associated with substantially elevated risks of the metabolic syndrome (dislipidemia, insulin resistance, hypertension), type 2 diabetes and cardiovascular disease in adulthood. The mechanisms of such "fetal origins" or "programming" of disease phenomenon remain unresolved. Too large size at birth seems also associated with an increased risk. Many known or suspected causes of or conditions associated with adverse (poor or excessive) fetal growth or preterm birth have been associated with oxidative stress. Plausibly, oxidative stress may be a common link underlying the superficial "programming" associations between adverse fetal growth or preterm birth and elevated risks of certain chronic diseases. The mechanisms of oxidative stress programming may be through directly modulating gene expression or indirectly through the effects of certain oxidized molecules. Experimental investigations have well demonstrated the role of redox balance in modulating gene expression, and recent studies indicate that both the insulin functional axis and blood pressure could be sensitive targets to oxidative stress programming. Adverse programming may occur without affecting fetal growth, but more frequently among low birth weight infants merely because they more frequently experienced known or unknown conditions with oxidative insults. As oxidative stress levels are easily modifiable during pregnancy and early postnatal periods (which are plausible critical windows), the hypothesis, if proved valid, will suggest new measures that could be very helpful on fighting the increasing epidemic of the metabolic syndrome, type 2 diabetes and cardiovascular disease. Currently, there are several ongoing large randomized trials of antioxidant supplementation to counter oxidative stress during pregnancy for the prevention of preeclampsia. It would be invaluable if long-term follow-ups of infants born to women in such trials could be realized to test the oxidative stress programming hypothesis in such experimental trial settings.     

Lipopolysaccharide inhibits macrophage phagocytosis of apoptotic neutrophils by regulating the production of tumour necrosis factor α and growth arrest-specific gene 6

Removal of apoptotic cells from inflammatory sites by macrophages is an important step in the resolution of inflammation. However, the effect of inflammatory modulators on phagocytic clearance of apoptotic cells remains to be clarified. In this paper, we demonstrate that lipopolysaccharide (LPS), a potent inflammatory agent, inhibits the phagocytosis of apoptotic neutrophils by mouse peritoneal macrophages. This inhibition can be attributed to both LPS-mediated induction of tumour necrosis factor (TNF-α) and suppression of growth arrest-specific gene 6 (Gas6) in macrophages. We found that LPS-induced TNF-α production inhibited phagocytic ability of macrophages in an autocrine manner. In contrast, Gas6 expression in macrophages was blocked by LPS, which also contributes to the inhibition of macrophage phagocytosis by LPS. Our data suggest that phagocytic clearance of apoptotic neutrophils by macrophages can be regulated by local pro- and anti-inflammatory factors in two opposite states.     

Inhibition of the release of soluble tumor necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-α antibody

The role of tumor necrosis factor- in the shedding of soluble tumor necrosis factor receptors in endotoxemia was investigated. The appearance of the soluble tumor necrosis factor receptors was assessed in four healthy volunteers following an intravenous injection of tumor necrosis factor- and in eight chimpanzees after intravenous administration of endotoxin in the absence or presence of concurrent treatment with a neutralizing anti-tumor necrosis factor- monoclonal antibody. Injection of tumor necrosis factor- in humans elicited a significant, instantaneous (after 15 min) increase in the plasma concentrations of both types of soluble tumor necrosis factor receptors. In chimpanzees, treatment with the anti-tumor necrosis factor- antibody completely neutralized endotoxin-induced tumor necrosis factor- activity. The release of soluble tumor necrosis factor receptors was strongly (80–90%) inhibited in the presence of the neutralizing antibody. Our results indicate that tumor necrosis factor- is a prime mediator of endotoxin-induced release of its own soluble receptors.     

Expression patterns of PSA-NCAM in the human ganglionic eminence and its vicinity: role of PSA-NCAM in neuronal migration and axonal growth?

The ganglionic eminence (GE) is a transient but conspicuous structure of the developing forebrain which not only gives rise to a large number of precursor neurons and glial cells for various structures of the forebrain, but in addition serves as an intermediate target for growing axons to the cerebral cortex. To investigate the roles of the highly polysialylated isoform of the neural cell adhesion molecule (PSA-NCAM) in cell migration and axonal growth within the GE and its neighbouring structures, the spatio-temporal expression pattern of PSA-NCAM was examined in human fetal forebrains between 14 and 36 weeks of gestation with a specific immunohistochemical method. Scattered PSA-NCAM-positive cells were found in the centre but more frequently in the marginal zone of the GE. Intensely labelled cells were also identified in the gangliothalamic body, basolateral nuclei of the amygdala and the subventricular and intermediate zone adjacent to the GE. This cellular immunoreactivity started to appear in various structures during the period from 14 to 19 weeks and gradually diminished after 25-28 weeks. Strong immunoreactivity was also detected in fibres running from the intermediate zone of the neocortex to the internal capsule from 16 weeks onwards, and after 24 weeks, the immunoreactivity was gradually decreased. In the vicinity of the GE, between 16 and 22 weeks, short fibre bundles were observed to leave the longitudinally oriented axons of the internal capsule to reach the marginal zone of the GE. Our results suggest a close relationship between PSA-NCAM expression and neuronal migration (over short distances) and transitory axonal projections (target recognition and axonal fasciculation) in the region of the GE.     

Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?

BACKGROUND: Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation. METHOD: Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent. CONCLUSIONS: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.     

Hyperactive night and day? Actigraphy studies in adult ADHD: a baseline comparison and the effect of methylphenidate

STUDY OBJECTIVES: To investigate parameters of sleep, activity, and circadian rhythm, as well as the effects of methylphenidate on these variables, in adults with ADHD. DESIGN: 1) Baseline group comparison; 2) Double blind, placebo-controlled, cross-over medication trial. SETTING: Data collection took place during daily lives of participants. PARTICIPANTS: 39 normal controls and 33 adults with ADHD for baseline comparisons; 31 adults with ADHD in medication trial. INTERVENTIONS: Treatment with placebo and methylphenidate during medication trial. MEASUREMENTS AND RESULTS: Actigraphy and sleep log data were collected for 7 consecutive nights and days to obtain baseline values for ADHD and normal controls. Repeated measurements during placebo and methylphenidate treatment were conducted for the ADHD group. Actigraphic sleep estimates showed that ADHD subjects took longer to fall asleep, had lower sleep efficiency, and had shorter within-night periods of uninterrupted sleep. These findings were consistent with subjective complaints. Actigraphic measures of ADHD subjects showed continuously elevated daytime activity levels, resulting in a 24-hour pattern that was more stable and less variable than in controls. Methylphenidate led to a later bedtime, later sleep onset, and reduction in sleep duration. However, number and total duration of nocturnal awakenings decreased, while mean duration of within-night periods of uninterrupted sleep increased, indicating more consolidated sleep. CONCLUSIONS: Our data suggest that sleep problems are inherent in adults with ADHD and that methylphenidate reduced total sleep time but improved sleep quality by consolidating sleep.     

Advanced glycation end-products disrupt the blood–brain barrier by stimulating the release of transforming growth factor–β by pericytes and vascular endothelial growth factor and matrix metalloproteinase–2 by endothelial cells in vitro

Diabetic encephalopathy is now accepted as an important complication of diabetes. The breakdown of the blood–brain barrier (BBB) is associated with dementia in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to identify the possible mechanisms responsible for the disruption of the BBB after exposure to advanced glycation end-products (AGEs). We investigated the effect of AGEs on the basement membrane and the barrier property of the BBB by Western blot analysis, using our newly established lines of human brain microvascular endothelial cell (BMEC), pericytes, and astrocytes. AGEs reduced the expression of claudin-5 in BMECs by increasing the autocrine signaling through vascular endothelial growth factor (VEGF) and matrix metalloproteinase–2 (MMP-2) secreted by the BMECs themselves. Furthermore, AGEs increased the amount of fibronectin in the pericytes through a similar up-regulation of the autocrine transforming growth factor (TGF)–β released by pericytes. These results indicated that AGEs induce basement membrane hypertrophy of the BBB by increasing the degree of autocrine TGF-β signaling by pericytes, and thereby disrupt the BBB through the up-regulation of VEGF and MMP-2 in BMECs under diabetic conditions.     

Acute and prolonged effects of TNF-α on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture

The pro-inflammatory cytokine TNF-α has multiple effects on adipocyte function, including the production of adipokines. In this paper, we have examined the acute vs prolonged effects of TNF-α on the expression and secretion of key inflammation-related adipokines by human adipocytes. Adipocytes differentiated in culture were treated with TNF-α for 1–24 h, mRNA quantitated by real-time polymerase chain reaction (PCR) and secreted adipokines by ELISA. Treatment of adipocytes with TNF-α for up to 24 h had little effect on MIF, MT-2 and PAI-1 mRNA levels. TNF-α decreased adiponectin, adipsin, haptoglobin and leptin mRNA levels by 24 h, but adiponectin and haptoglobin mRNA was initially increased. In contrast, TNF-α induced rapid and substantial increases in expression of the genes encoding IL-6, MCP-1, NGF and TNF-α itself; IL-6 and TNF-α mRNA levels peaked at 2 h with 75-fold and 600-fold increases, respectively. The elevated MCP-1, NGF and VEGF mRNA levels were sustained between 4 and 24 h. The adipokine secretion pattern largely paralleled cellular mRNA levels; IL-6 (transiently), MCP-1, NGF and VEGF release were stimulated by TNF-α, with an accelerating rate of MCP-1 secretion over 24 h. TNF-α has rapid and substantial effects on the synthesis of key inflammation-related adipokines in human adipocytes, with highly gene-specific responses.     

Atherosclerosis in the vertebral artery: an intrinsic risk factor in the use of spinal manipulation?

The presence of atherosclerotic plaques and their influence on the vertebral artery is of clinical importance within the scope of spinal manipulation. Manipulation may stimulate the development of atherosclerotic plaques, could detach an embolus with ensuing infarction, injure the endothelium or may directly cause a dissection in the presence of atherosclerotic plaques. In order to identify the sites and frequency of atherosclerotic plaques and to determine its relation to the tortuous course of the vertebral artery, a cadaveric study was performed. The vertebral arteries of 57 human cadavers were studied. The vertebral artery was virtually divided into four segments: the pre-vertebral (V1), the vertebral (V2), the atlanto-axial (V3), and the intracranial segment (V4). Abnormalities in the origin and course of the vertebral artery were noted, along with any associated osseous, or cartilaginous anomalies in the neck. After dissection, the artery was opened and macroscopically screened for the presence of atherosclerotic plaques. In 22.8% of the cases, no atherosclerotic plaques were present. In 35.1% of the cases, the atherosclerotic plaques were unilateral, of which 60.0% was on the left side, 40.0% on the right side, and in 42.1%, the occurrence was bilateral. Atherosclerotic plaques were significantly more present in the V3 segment than in the V1 (0.007) and V2 segment (0.049). In the V1 (P=0.008) and V2 segment (P=0.002), there was a correlation between a tortuous course of the vessel and the occurrence of atherosclerotic plaques. In individuals with marked atherosclerotic disease, stretching and compression effects of rotational manipulative techniques on atherosclerotic vessels impose a further risk factor for vertebrobasilar insufficiency. As direct evidence of atherosclerotic plaques are rarely available, therapists should avoid manipulative techniques at all levels of the cervical spine in the presence of any indirect sign of atherosclerotic disease or in the presence of calcified arterial walls or tortuosities of the vessels visible on routinely available X-ray images of the cervical or thoracic spine. It is strongly recommended, that if any doubt exists about the nature of a clinical presentation, vigorous manual procedures should be avoided until either the diagnosis is definitive or gentle manual therapy has proven effective.     

Sertoli cell proliferation in the fetal and neonatal rat testis: a continuous phenomenon?

Sertoli cell population kinetics, as evidenced by semi-quantitative immunolabeling for proliferating cell nuclear antigen (PCNA) and Ki-67, in developing Wistar rat male gonads of embryos and neonates [14.5 days post conception (dpc)-7 days post partum (dpp)], was investigated. Throughout the examined period a gradual increase of immunolabeled Sertoli cell number, associated with intense mitotic activity, was observed. PCNA labeling index of Sertoli cells increased from 66.67 (at 14.5 dpc) to 89.74 (at 18.5 dpc) and then dropped to 75.24 (at 20.5 dpc). At birth, the percentage of PCNA immunoreactive Sertoli cells reached 98.70% and remained high thereafter, attaining a peak value of 99.90% at 7 dpp. The percentage of Ki-67 immunoreactive Sertoli cells in the fetal testis increased from E14.5 (43.95%) to E20.5 (77.40%). The proliferation rate did not alter considerably in the neonatal testis until 5 dpp. At this point, a significant increase of the Ki-67 labeling index was observed and a peak value of 95.76% was reached at 7 dpp. The pattern of Sertoli cell proliferation with age and the establishment of the final Sertoli cell number in vivo established in the present study was compared to the results from earlier investigations reported in the literature and the observed fluctuation of dividing cell numbers, associated with immunolabeling results throughout the examined period, complements and extends existing data. An appraisal of the timing of Sertoli cell proliferation in other species, namely mouse and man, is presented. The current investigation may be useful in evaluating the potential influence of factors interfering with normal mitotic activity of Sertoli cells, including cell selection mechanisms, such as apoptosis, senescence, DNA repair and hormonal/paracrine growth modulation.